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Abstract The only current strategy to test efficacy of novel interventions for sustained HIV control without antiretroviral therapy (ART) among people with HIV (PWH) is through an analytical treatment interruption (ATI). Inclusion of ‘placebo’ controls in ATIs poses ethical, logistical, and economic challenges. To understand viral dynamics and rates of post-treatment control (PTC) after ATI among PWH receiving either placebo or no intervention, we undertook an individual-participant data meta-analysis. In total, 24 eligible prospective studies with 382 individuals with ≥5 plasma HIV RNA viral loads (pVLs) within the first 84 days post-ATI were included. Early-ART was defined as ART initiation within 6 months of HIV acquisition; others were classified as late-ART or unknown. Median age was 42 years, 91% male, 75% white, 45% received early-ART. Median time to pVL >50, >400, and >10,000 copies/mL was 16 days (interquartile range [IQR]:13–25), 21 (IQR:15–28), and 32 (IQR:20–35), respectively. PTC defined as pVL

Abstract With advanced mass spectrometry (MS)-based proteomics, genome-scale proteome coverage can be achieved from bulk tissues. However, such bulk measurement lacks spatial resolution and obscures tissue heterogeneity, precluding proteome mapping of tissue microenvironment. Here we report an integrated wet collection of single microscale tissue voxels and Surfactant-assisted One-Pot voxel processing method termed wcSOP for robust label-free single voxel proteomics. wcSOP capitalizes on buffer droplet-assisted wet collection of single voxels dissected by LCM to the tube cap and SOP voxel processing in the same collection cap. This method enables reproducible, label-free quantification of approximately 900 and 4600 proteins for single voxels at 20 µm × 20 µm × 10 µm (~1 cell region) and 200 µm × 200 µm × 10 µm (~100 cell region) from fresh frozen human spleen tissue, respectively. It can reveal spatially resolved protein signatures and region-specific signaling pathways. Furthermore, wcSOP-MS is demonstrated to be broadly applicable for OCT-embedded and FFPE human archived tissues as well as for small-scale 2D proteome mapping of tissues at high spatial resolutions. wcSOP-MS may pave the way for routine robust single voxel proteomics and spatial proteomics.

Abstract Over 50% of individuals with lower limb loss report a fear of falling and avoiding daily activities partly due to a lack of plantar sensation. Providing direct somatosensory feedback via neural stimulation holds promise for addressing this issue. In this study, three individuals with lower limb loss received a sensory neuroprosthesis (SNP) that provided plantar somatosensory feedback corresponding to prosthesis-floor interactions perceived as arising from the missing foot generated by electrically activating the peripheral nerves in the residuum. Participants walked on a treadmill while receiving perturbations involving brief increases in the belt speed. Perturbations were initiated during early stance and randomly delivered to intact and prosthetic sides with the SNP active or inactive. With the SNP active, participants exhibited decreased trunk angular sway and peak trunk flexion angular velocity during recovery from both prosthetic and intact side perturbations. For prosthetic side perturbations, peak ground reaction force magnitudes decreased when the SNP was active. For intact side perturbations, peak ground reaction force magnitudes increased on the prosthetic side’s first recovery step after the perturbation, which resulted in a more symmetric recovery because the force approached the response on the intact side’s first recovery step following a prosthetic side perturbation. These results suggest participants integrated the feedback from the SNP into their sensorimotor control for maintaining stability and gained confidence in relying on their prosthetic limb during recovery. Restoring plantar sensation with a SNP for individuals with lower limb loss could lead to reduced risk of falling by improving recovery from trips.

Abstract Single-cell multiomics provides comprehensive insights into gene regulatory networks, cellular diversity, and temporal dynamics. Here, we introduce nanoSPLITS (nanodroplet SPlitting for Linked-multimodal Investigations of Trace Samples), an integrated platform that enables global profiling of the transcriptome and proteome from same single cells via RNA sequencing and mass spectrometry-based proteomics, respectively. Benchmarking of nanoSPLITS demonstrates high measurement precision with deep proteomic and transcriptomic profiling of single-cells. We apply nanoSPLITS to cyclin-dependent kinase 1 inhibited cells and found phospho-signaling events could be quantified alongside global protein and mRNA measurements, providing insights into cell cycle regulation. We extend nanoSPLITS to primary cells isolated from human pancreatic islets, introducing an efficient approach for facile identification of unknown cell types and their protein markers by mapping transcriptomic data to existing large-scale single-cell RNA sequencing reference databases. Accordingly, we establish nanoSPLITS as a multiomic technology incorporating global proteomics and anticipate the approach will be critical to furthering our understanding of biological systems.

Abstract Background Preterm birth (PTB) is a serious health problem. PTB complications is the main cause of death in infants under five years of age worldwide. The ability to accurately predict risk for PTB during early pregnancy would allow early monitoring and interventions to provide personalized care, and hence improve outcomes for the mother and infant. Objective This study aims to predict the risks of early preterm (

Abstract Jurassic and Palaeocene tidal deposits of the epeiric Western Interior Sea in Wyoming, USA, differ significantly due to their contrasting climates and tectonic, geographic and depositional settings. Tidally generated, cross‐bedded sandstone bodies contained by incisions are common to both settings and can potentially be uncritically attributed to marine flooding of fluvial systems. Key differences in lithology, ichnology and relationships with surrounding sediment reveal fundamentally different depositional settings, however. The Jurassic system occupied a low accommodation, semi‐arid environment, with geographically open shorelines as relative sea‐level fell, creating an unconformable contact with the underlying, storm wave‐dominated shelf and shoreface deposits. Siliciclastic, intertidal flats formed adjacent to coastal aeolian and fluvial environments during brief turnarounds from the degradational (forced regressive) to aggradational and retrogradational (transgressive) system tract. Basinward of these environments, metre to decimetre‐scale cross‐bedded, bioclastic, subtidal compound dunes and tidal inlet complexes accumulated in areas of minimal clastic flux and within incisions created by submarine tidal currents. By contrast, the Palaeocene tidal systems formed in a high accommodation, subtropical setting, as rising sea levels forced the fluvial to marine transition zone landward and flooded coastal swamps, forming geographically irregular, back‐barrier complexes and tidally influenced fluvial systems. High volumes of siliciclastics, terrigenous organic material and freshwater were delivered by the rivers and created physicochemical stress on the marine embayments. Sandy tidal flat deposits accumulated in lagoons and interdistributary bays, but unlike the Jurassic examples, they do not mark a turnaround from the falling stage to the transgressive system tract. The potential preservation window for tidalites is significantly greater vertically in the aggradational to retrogradational setting than in the degradational system due to greater accommodation. The preservation window is vertically smaller, but areally greater in the Jurassic, forced regressive system because of basinward enhancement of tidal currents driven by complex palaeobathymetry caused by tectonic activity of local pre‐Laramide uplifts.

Creating a global workforce is a driving need for our time. Higher education institutions are prioritizing helping students develop an awareness of their own and other cultures, as they are expected to participate in a diverse workforce. This study examines a large data set of learning assessment data for undergraduate students from an agriculture course focused on diversity and social justice, using the Beliefs, Events and Values Inventory (BEVI) instrument to assess the multicultural awareness development of the students. The study compared the impact of the medium of instruction (face-to-face versus online) in helping students develop multicultural awareness. The results revealed that students did not differ much in multicultural awareness across the medium of instruction. Moreover, to understand the multicultural awareness of the students in the pre-COVID period, during COVID and in the post-COVID period, the pre-test BEVI scores of the students were compared using ANOVA. The goal of this analysis was to capture the change in worldview of the students from the pre-COVID period to during COVID and post-COVID periods. The results revealed that pre-test BEVI scores for the pre-COVID period showed a lower degree of multicultural awareness than students during the COVID and post-COVID times. Also, there was no significant difference in the pre-test BEVI scores for the students in the COVID and post-COVID periods. Overall, the study makes important contributions to higher education literature as it reveals that (1) medium has negligible impact on the multicultural awareness of the students, and that (2) student worldviews have shifted significantly since the height of the global pandemic.

Abstract Recognition of compound delta clinoforms has led to a new understanding of delta progradation and architecture. Limited study has been dedicated to spatially delineate three dimensional morphologies of subaqueous deltas and their migration away from active sediment sources. Qualitative and quantitative analyses of 38 Holocene deltas lead to the observation of two main gradient breaks at tens-of-meters water depth and variable subaqueous geometries. Geometric variability was captured relative to riverine-sediment sources and basinal energies and presents steeper shoreline and subaqueous delta clinoforms, reaching 1°, separated by a gently-dipping 0.11° platform with widths from few kilometers (Ebro Delta) to 200 kilometers (Amazon Delta). In wave-dominated systems, the platform is absent ahead of the sediment source but widens laterally away as a smooth arcuate surface, whereas in tide-dominated systems the platform widens ahead of active sources and narrows ahead of starved ones while hosting erosional features and tidal channel/bar couplets.

Summary: Background: Children from racial and ethnic minority groups are at greater risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but it is unclear whether they have increased risk for post-acute sequelae of SARS-CoV-2 (PASC). Our objectives were to assess whether the risk of respiratory and neurologic PASC differs by race/ethnicity and social drivers of health. Methods: We conducted a retrospective cohort study of individuals

IntroductionMacrophages play an important role in disease progression of pediatric cholestatic liver disease, particularly biliary atresia (BA); however, the restorative versus pathogenic role for precise macrophage subsets remains poorly defined. We aimed to distinguish the transcriptional profiles and roles of defined macrophage subset(s) in murine BA.MethodsWe used multiparameter flow cytometry and RNA-sequencing analysis to profile recruited CD11bhiCD64+ hepatic macrophages by cell surface expression of MHCII and Ly6c in the Rhesus rotavirus (RRV)-induced murine model of BA versus saline controls. Modulation of macrophage numbers via intra-peritoneal injections of clodronate-loaded liposomes was performed to determine the association between macrophage numbers and histologic injury (Ishak score).ResultsLy6c+ macrophages demonstrated the greatest increase in numbers and percent of total macrophages in murine BA versus saline controls whereas MHCII+ macrophages decreased. Transcriptional changes in murine BA MHCII+ macrophages included reduced expression of the Kupffer cell gene signature, lower expression of genes involved in homeostatic processes, and increased expression of genes involved in inflammatory processes. Ly6c+ macrophages in murine BA showed increased expression for Hif1a and other genes involved in the cellular response to hypoxia. Among all subsets, the number of Ly6c+ macrophages exhibited the strongest correlation with severity of histologic liver injury by Ishak score.ConclusionsOur data identify specific pathways upregulated in Ly6c vs MHCII+ macrophage subsets in murine BA. Transcriptional similarities between murine BA and human cholestatic macrophages may enable translation of future mechanistic studies to new macrophage subset-specific therapies.

This study compared the Peak Health and Performance curriculum (PHP) to the Teen Cuisine curriculum (TC) on improving nutrition, food safety, and physical activity (PA) behaviors among youth. The quasi-experimental study was conducted in Michigan middle and high schools and included 1007 5th- through 12th-grade students, who participated in either the PHP or the TC curriculum. There were 465 students in the PHP group and 495 students in the TC group. Nutrition, food safety, and PA behaviors were surveyed before and after each program. Individual curriculum pre- and post-scores were compared using a paired t-test, and between-group changes were examined using a repeated-measures ANOVA. Missing data were excluded case-wise. The results showed that vegetable and fruit consumption significantly increased for both groups. Washing vegetables before consumption and putting food back into the refrigerator within 2 hours increased in the PHP vs the TC group; however, there was not a significant group difference. PA behaviors increased for the TC group, but not for the PHP group. Both the PHP and the TC were shown to be effective in increasing vegetable and fruit consumption among Michigan youth. Further, the PHP improved food safety practices, while the TC increased PA behaviors.

Purpose:. To determine if dual-degree training [ie, completion of a National Institutes of Health (NIH)-funded MD/PhD program], among other professional development and demographic variables, predicted academic productivity (eg, K-to-R conversion, number of publications, etc.) among early-career surgeon-scientists. Methods:. We analyzed publicly available data from the National MD/PhD Program Outcomes Study and the Association of American Medical Colleges Graduate Medical Education Track database to identify trends in the number and proportion of MD/PhD graduates pursuing surgical specialties. NIH Research Portfolio Online Reporting Tool Expenditures and Results was interrogated to identify a cohort of early-career academic surgeon-scientists receiving K-awards from 2011 to 2021. Results:. The total number of MD/PhD program graduates completing Graduate Medical Education training increased each decade after the Medical Scientist Training Program was established by the National Institute of General Medical Sciences, but the proportion completing surgical specialties did not change significantly (P = 0.96) from 1965 to 2014. More recent residency match trends demonstrate an increase in both the proportion and number of MD/PhD graduates entering surgical specialties, with 21.5% entering surgical residency training in 2020. Among 476 early-career academic surgeon-scientists receiving K-awards at 70 institutions, 27% were faculty members at only 4 universities, suggesting that federally funded surgeon-scientists are concentrated at a small number of institutions. Although MD/PhD graduates represented only 2.3% of active surgical residents from 2011 to 2020, they constituted a much higher fraction of K-awardees (29%). Of 296 surgeon-scientists who completed K-awards, 35% successfully obtained an R01-equivalent award. Conclusions:. These findings emphasize the need for comprehensive career development and institutional resources to support early-career surgeon-scientists.

It has been demonstrated that helminths are capable of critically impacting the fitness of their hosts. This has typically been shown experimentally through the administration of anthelmintic drugs but are rarely performed on a landscape or host population scale. Here, the anthelmintic fenbendazole (FBZ) was mixed in a supplemental feed and provided to a free-ranging population of Northern bobwhite quail (Colinus virginianus). Abundances of Northern bobwhite and two nematode parasites commonly found infecting Northern bobwhite were monitored and compared to a neighboring untreated population. The Northern bobwhite population receiving the medicated feed grew substantially from 2019 to 2022, while the neighboring site had no change in abundance. The treated population was also substantially greater than the untreated population in 2021 and 2022. Additionally, the treated Northern bobwhite population had substantially lower abundances of the two nematodes. This research provides evidence of the ability of helminth populations to have a negative impact on Northern bobwhite populations and presents a method for reducing helminth abundance in those populations on a landscape scale.

ObjectiveTo examine the social determinants of early childhood caries (ECC), one of the greatest public health risks affecting children, and examine alternative pathways of influence.MethodsA physically healthy, socio-demographically high-risk sample of initially caries-free children, aged 1–4 years, was prospectively studied for 2 years. At 6-month intervals, assessments were made of caries presence from a standard dental exam; oral microbiology was assayed from saliva samples; oral hygiene behaviors and psychological and psychosocial risk exposure were derived from interviews and questionnaires.Results189 children were enrolled; ECC onset occurred in 48 children over the 2-year study period. A composite measure of psychosocial risk was significantly associated with ECC onset over the course of the study (1.57, 95% CI 1.12–2.20, p

The pursuit of translational biomarkers is complex due to the heterogeneous human pathophysiology, but critical for disease diagnosis, prognosis, monitoring therapeutic efficacy, and for patient stratification. In HIV-associated neurocognitive impairment (NCI), biomarkers that delineate the trajectory of neuropathogenesis and neurocognitive sequelae are critical, particularly considering confounders such as substance use, including Methamphetamine (METH). METH use is a significant health concern among persons living with HIV (PWH), aggravating cognitive deficits and neuroinflammation despite of antiretrovirals, introducing elements in the microenvironment that are fundamentally differerent in relation to non-METH users, such as high levels of dopamine (DA) affecting HIV-innate immune targets. Yet, current biomarkers do not detect these differences. We hypothesized that predefined DA-induced signatures detectable in peripheral blood leukocytes, can distinguish HIV+ METH users compared to HIV-negative or PWH that are non METH users. The elevated expression of CD8A, CREBBP, CCL5, and combinations of dopaminergic pathway transcripts clustered METH users with detectable CSF viral load and major depressive disorder (MDD), indicating neuroimmune-mechanistic links. Cathecol-o-methyltransferase (COMT) gene polymorphisms affecting DA metabolism improved the identification of PWH using METH with biomarkers. The results indicate that underlying immunedopaminergic mechanisms provide signatures and genotypes that can identify PWH that are METH users and their attributes.

Background Orofacial pain is a specialty of dentistry that often encounters complex symptoms beyond the scope of dental practice, indicating a role for interprofessional teams in treating chronic orofacial pain.Discussion Interprofessional teams often include specialists from neurology, physical therapy, sleep medicine, and behavioral medicine, among others. Interprofessional practices can be difficult to achieve and require a commitment of communication, collaboration, co-location, and organizational support. A complex chronic orofacial pain case exemplifies the challenges for patients receiving sequential or siloed care, including delays in diagnosis, invasive procedures, and worsened disability. Common barriers to collaborative care and possible steps to close these gaps are discussed..

Northern bobwhite quail (Colinus virginianus) are an economically significant gamebird that has experienced continued general decline in the Rolling Plains ecoregion of Texas. Habitat loss and changing environmental conditions have been cited as major contributors to this decline, with factors such as parasites being considered inconsequential. To better assess the impacts of parasite infections on bobwhite populations in the Rolling Plains, bobwhite abundance was monitored in response to anthelminthic treatment. With the prevalence of Oxyspirura petrowi and Aulonocephalus pennula infections in quail from Mitchell County, Texas confirmed by previous studies, the anthelminthic agent Fenbendazole was introduced as a means of parasite control in 2014–2015. Bobwhite abundance was determined through a series of call counts which provided an index of bobwhite populations and were conducted throughout the course of the study. In 2016, call counts revealed a significant increase of bobwhite in the area subject to Fenbendazole treatment, while untreated areas showed no changes in abundance. Fall populations of bobwhite in the treated zone approached 300% of those in untreated areas, these findings suggest that parasites may have a more significant impact on quail populations in the Rolling Plains than previously suspected. With the importance of bobwhite as a game bird in the Rolling Plains, the potential impacts of parasites must be taken into consideration as a factor contributing to bobwhite declines. Further research into the long-term effects these parasites have on quail populations in the ecoregion may aid landowners in developing affordable and effective conservation strategies.

Abstract Background Biologic strain such as oxidative stress has been associated with short leukocyte telomere length (LTL), as well as with preeclampsia and spontaneous preterm birth, yet little is known about their relationships with each other. We investigated associations of postpartum maternal LTL with preeclampsia and spontaneous preterm birth. Methods This pilot nested case control study included independent cohorts of pregnant people with singleton gestations from two academic institutions: Cohort 1 (hereafter referred to as Suburban) were enrolled prior to 20 weeks’ gestation between 2012 and 2018; and Cohort 2 (hereafter referred to as Urban) were enrolled at delivery between 2000 and 2012. Spontaneous preterm birth or preeclampsia were the selected pregnancy complications and served as cases. Cases were compared with controls from each study cohort of uncomplicated term births. Blood was collected between postpartum day 1 and up to 6 months postpartum and samples were frozen, then simultaneously thawed for analysis. Postpartum LTL was the primary outcome, measured using quantitative polymerase chain reaction (PCR) and compared using linear multivariable regression models adjusting for maternal age. Secondary analyses were done stratified by mode of delivery and self-reported level of stress during pregnancy. Results 156 people were included; 66 from the Suburban Cohort and 90 from the Urban Cohort. The Suburban Cohort was predominantly White, Hispanic, higher income and the Urban Cohort was predominantly Black, Haitian, and lower income. We found a trend towards shorter LTLs among people with preeclampsia in the Urban Cohort (6517 versus 6913 bp, p = 0.07), but not in the Suburban Cohort. There were no significant differences in LTLs among people with spontaneous preterm birth compared to term controls in the Suburban Cohort (6044 versus 6144 bp, p = 0.64) or in the Urban Cohort (6717 versus 6913, p = 0.37). No differences were noted by mode of delivery. When stratifying by stress levels in the Urban Cohort, preeclampsia was associated with shorter postpartum LTLs in people with moderate stress levels (p = 0.02). Conclusion Our exploratory results compare postpartum maternal LTLs between cases with preeclampsia or spontaneous preterm birth and controls in two distinct cohorts. These pilot data contribute to emerging literature on LTLs in pregnancy.

Quiescence is a reversible cell cycle exit traditionally thought to be associated with a metabolically inactive state. Recent work in muscle cells indicates that metabolic reprogramming is associated with quiescence. Whether metabolic changes occur in cancer to drive quiescence is unclear. Using a multi-omics approach, we found that the metabolic enzyme ACSS2, which converts acetate into acetyl-CoA, is both highly upregulated in quiescent ovarian cancer cells and required for their survival. Indeed, quiescent ovarian cancer cells have increased levels of acetate-derived acetyl-CoA, confirming increased ACSS2 activity in these cells. Furthermore, either inducing ACSS2 expression or supplementing cells with acetate was sufficient to induce a reversible quiescent cell cycle exit. RNA-Seq of acetate treated cells confirmed negative enrichment in multiple cell cycle pathways as well as enrichment of genes in a published G0 gene signature. Finally, analysis of patient data showed that ACSS2 expression is upregulated in tumor cells from ascites, which are thought to be more quiescent, compared to matched primary tumors. Additionally, high ACSS2 expression is associated with platinum resistance and worse outcomes. Together, this study points to a previously unrecognized ACSS2-mediated metabolic reprogramming that drives quiescence in ovarian cancer. As chemotherapies to treat ovarian cancer, such as platinum, have increased efficacy in highly proliferative cells, our data give rise to the intriguing question that metabolically-driven quiescence may affect therapeutic response.

Introduction Inadequate treatment of enlarged lateral lymph nodes (LLNs) in rectal cancer patients is associated with an increased lateral local recurrence (LLR) risk, despite neoadjuvant treatment and total mesorectal excision (TME) surgery. There is a promising role for LLN dissection (LLND) to lower this risk, but this challenging procedure requires appropriate training. This study protocol describes a prospective evaluation of oncological outcomes after standardised treatment based on multidisciplinary training, thereby aiming for a 50% reduction in LLR rate.Methods and analysis A prospective registration study will be opened in hospitals in which the involved multidisciplinary team members (radiologists, radiation oncologists, surgeons and pathologists) have received dedicated training to enhance knowledge and awareness of LLNs and in which standardised treatment including LLND has been implemented. Patients with rectal cancer and at least one enlarged LLN (short-axis ≥7.0 mm), or intermediate LLN (short-axis 5.0–6.9 mm) with at least one malignant feature on primary MRI, evaluated by a trained radiologist, are eligible. Patients will undergo neoadjuvant treatment by trained radiation oncologists, followed by TME surgery in combination with a minimally invasive, nerve-sparing LLND performed by trained surgeons. LLND specimens are evaluated by trained pathologists or grossing assistants. The primary outcome is LLR rate 3 years postoperatively. Secondary outcomes are morbidity, disease-free survival, overall survival and quality of life. To demonstrate a significant reduction in LLR rate from 13% (based on historical control data) to 6% after optimised treatment, 200 patients with enlarged LLNs are required.Ethics and dissemination The medical ethics board of the Vrije Universiteit Medical Centre (VUMC), the Netherlands, approved the study on 23 November 2022 (reference: 2021.0524). Participating centres must obtain local approval and participants are required to provide written informed consent. Results obtained from this study will be communicated via peer-reviewed medical journals and presentations at conferences.Trail registration number NCT04486131, 24 July 2020, https://clinicaltrials.gov/ct2/show/NCT04486131.

Digital healthcare has rapidly evolved during and in the post-COVID pandemic era, expanding the roles and responsibilities of community pharmacists. Services like telepharmacy, e-prescriptions, remote medication therapy management, and digital monitoring of chronic conditions, have evolved into everyday routine pharmacy practices. Pharmacists are at the forefront and the most accessible healthcare professionals for patients and are increasingly pivotal in providing comprehensive patient care, including digital patient care services. To ensure that future generations of pharmacists are digitally competent, it is crucial that digital health education is provided to pharmacy students. Furthermore, fostering high-quality multidisciplinary research, particularly in collaboration with medicine and other health disciplines, is essential for advancing the digital health skills of the future pharmacy workforce. Despite the growing use of digital health technologies, there are significant between-country differences in digital health education, the clinical settings in which digital health technologies are used, and their implementation in day-to-day practice. This commentary summarizes key insights from the International Digital Health Workshop held at the University of Sydney in November 2023. To help ensure pharmacists are included as participants in future digital health research, recent advances in digital health education and interprofessional research projects across three universities from far-off world regions were presented. Participants discussed a possible collaborative, interprofessional, and international research project on chronic disease prevention using digital health technologies. The need for interdisciplinary digital health curricula was highlighted in the workshop discussions, specifically tailored to address the knowledge requirements of pharmacists and other healthcare professionals.

Abstract Adverse pregnancy outcomes (APOs) affect a large proportion of pregnancies and represent an important cause of morbidity and mortality worldwide. Yet the pathophysiology of APOs is poorly understood, limiting our ability to prevent and treat these conditions. To search for genetic markers of maternal risk for four APOs, we performed multi-ancestry genome-wide association studies (GWAS) for pregnancy loss, gestational length, gestational diabetes, and preeclampsia. We clustered participants by their genetic ancestry and focused our analyses on three sub-cohorts with the largest sample sizes: European, African, and Admixed American. Association tests were carried out separately for each sub-cohort and then meta-analyzed together. Two novel loci were significantly associated with an increased risk of pregnancy loss: a cluster of SNPs located downstream of the TRMU gene (top SNP: rs142795512), and the SNP rs62021480 near RGMA. In the GWAS of gestational length we identified two new variants, rs2550487 and rs58548906 near WFDC1 and AC005052.1, respectively. Lastly, three new loci were significantly associated with gestational diabetes (top SNPs: rs72956265, rs10890563, rs79596863), located on or near ZBTB20, GUCY1A2, and RPL7P20, respectively. Fourteen loci previously correlated with preterm birth, gestational diabetes, and preeclampsia were found to be associated with these outcomes as well.

Abstract Background Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer death among women globally. Despite advances, there is considerable variation in clinical outcomes for patients with non-luminal A tumors, classified as difficult-to-treat breast cancers (DTBC). This study aims to delineate the proteogenomic landscape of DTBC tumors compared to luminal A (LumA) tumors. Methods We retrospectively collected a total of 117 untreated primary breast tumor specimens, focusing on DTBC subtypes. Breast tumors were processed by laser microdissection (LMD) to enrich tumor cells. DNA, RNA, and protein were simultaneously extracted from each tumor preparation, followed by whole genome sequencing, paired-end RNA sequencing, global proteomics and phosphoproteomics. Differential feature analysis, pathway analysis and survival analysis were performed to better understand DTBC and investigate biomarkers. Results We observed distinct variations in gene mutations, structural variations, and chromosomal alterations between DTBC and LumA breast tumors. DTBC tumors predominantly had more mutations in TP53, PLXNB3, Zinc finger genes, and fewer mutations in SDC2, CDH1, PIK3CA, SVIL, and PTEN. Notably, Cytoband 1q21, which contains numerous cell proliferation-related genes, was significantly amplified in the DTBC tumors. LMD successfully minimized stromal components and increased RNA–protein concordance, as evidenced by stromal score comparisons and proteomic analysis. Distinct DTBC and LumA-enriched clusters were observed by proteomic and phosphoproteomic clustering analysis, some with survival differences. Phosphoproteomics identified two distinct phosphoproteomic profiles for high relapse-risk and low relapse-risk basal-like tumors, involving several genes known to be associated with breast cancer oncogenesis and progression, including KIAA1522, DCK, FOXO3, MYO9B, ARID1A, EPRS, ZC3HAV1, and RBM14. Lastly, an integrated pathway analysis of multi-omics data highlighted a robust enrichment of proliferation pathways in DTBC tumors. Conclusions This study provides an integrated proteogenomic characterization of DTBC vs LumA with tumor cells enriched through laser microdissection. We identified many common features of DTBC tumors and the phosphopeptides that could serve as potential biomarkers for high/low relapse-risk basal-like BC and possibly guide treatment selections.

Comet C/2017 K2 (Pan-STARRS) provided a rare opportunity to investigate the evolution of coma composition and outgassing patterns over a transitional heliocentric distance ( R _h ) range where activity drivers in comets are thought to change from “hypervolatile” (CO, CH _4 , C _2 H _6 , and/or CO _2 )-dominated to H _2 O-dominated. We performed high-resolution ( $\lambda $ / ${\rm{\Delta }}\lambda $ ≈ 25,000–42,000), cross-dispersed, near-infrared spectroscopy of C/2017 K2 with iSHELL at the NASA Infrared Telescope Facility and NIRSPEC at the W. M. Keck II Observatory. We report gas rotational temperatures ( T _rot ) and molecular production rates ( Q ; molecules per second) or upper limits for the “hypervolatile” species CH _4 , CO, and C _2 H _6 , together with less volatile ices (CH _3 OH, H _2 O, HCN, C _2 H _2 , NH _3 , and OCS) over a range of pre-perihelion distances, R _h = 3.15–2.35 au. We also report (or stringently constrain) abundance ratios (mixing ratios) of the targeted species with respect to CO, C _2 H _6 , and (when detected) H _2 O. All volatiles were enriched relative to water in C/2017 K2 when compared to their mean values among Oort Cloud comets, whereas abundances relative to C _2 H _6 were consistent with their average values from other long-period comets.

Background: The increasing prevalence of drug-resistant tuberculosis (TB) underscores the urgent need for novel antimicrobial agents. Methods: This study integrates cultivation optimization, nuclear magnetic resonance (NMR) fingerprinting, and principal component analysis (PCA) to explore microbial secondary metabolites as potential anti-TB agents. Results: Using the combined approach, 11 bioactive compounds were isolated and identified, all exhibiting anti-Mycobacterium bovis BCG activity. Notable findings include borrelidin, a potent threonyl-tRNA synthetase inhibitor with broad biological activities, and L-O-Lac-L-Val-D-O-Hiv-D-Val, a peptide isolated for the first time from a plant endophyte, demonstrating broad-spectrum antimicrobial activity. Additionally, elaiophylin and polycyclic tetramate macrolactams (PTMs) displayed significant bactericidal effects, with elaiophylin achieving complete BCG inhibition at 72 h and PTMs marking their first reported anti-TB activity. The study also identified bafilomycins as potent scaffolds for anti-TB drug development, showcasing rapid bactericidal activity at low MIC values. Conclusions: These findings emphasize the value of microbial metabolites as a reservoir of bioactive compounds and provide new avenues for developing next-generation anti-TB therapies.

Background/Objectives: HIV-associated neurocognitive impairment (NCI) remains a prevalent issue among people with HIV (PWH) despite advancements in antiretroviral therapy (ART). The pathogenesis of HIV-associated NCI is linked to chronic neuroinflammation caused by HIV, even in those with successful viral suppression. Growth Differentiation Factor 15 (GDF15), a protein involved in inflammatory and metabolic stress responses, has emerged as a key player and potential biomarker for various neurological conditions. This study investigates the relationship between GDF15 expression and HIV-associated NCI. Methods: PWH from the California NeuroAIDS Tissue Network (CNTN) underwent comprehensive neuropsychological exams within 12 months before death and were categorized based on cognitive performance. We examined GDF15 levels in their CSF (Cerebrospinal Fluid) and brain tissues using immunoblotting, immunohistochemistry, double immunolabeling, and ELISA. Results: The cohort was of a similar age across HIV-associated NCI statuses (mean = 40.5), with a predominance of males (77%). The mean plasma viral load was 3.56 log10 copies/mL for Neurocognitively Unimpaired (NUI) PWH and 5.38 log10 copies/mL for people with HIV-associated NCI. GDF15 protein levels were significantly elevated in the frontal cortices of PWH with NCI compared to NUI PWH. Conclusions: The findings indicate that GDF15 may play a role in the pathogenesis of HIV-associated NCI, possibly through neuroinflammatory mechanisms. The strong association between GDF15 levels and cognitive impairment severity suggests its potential as a biomarker for the early detection and monitoring of NCI in PWH.

Background and purpose: Chronic postsurgical pain after total knee arthroplasty (TKA) is frequent and may be reduced by pain neuroscience education (PNE), teaching people about pain from a neurobiological perspective. This study investigated primarily the effectiveness of 2 individual sessions of PNE versus usual care on pain levels 3 months postoperatively in patients undergoing TKA. Secondary outcomes were physical functioning, stiffness, health-related quality of life, pain catastrophizing, attention to pain, and levels of anxiety and depression. Methods: A prospective single-center, parallel-group randomized controlled trial was undertaken including patients aged 18 years or older scheduled for primary TKA. 68 patients were randomly assigned to PNE or usual care. The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score 3 months postoperatively. Outcomes were measured preoperatively, at 2 weeks (acute phase), and at 3 and 12 months postoperatively. Results: We found no statistically significant difference (0.4 points; 95% confidence interval [CI] –1.7 to 2.4) in WOMAC pain scores 3 months after TKA between the PNE and control group. We found a statistically significant difference between the 2 groups for attention to pain at 3 months in favor of PNE (P = 0.02). Conclusion: This RCT showed that PNE was not superior to usual care in terms of reducing pain at 3 months after TKA. Attention to pain, as a secondary outcome, was significantly lower in the PNE group compared with usual care. Other secondary outcome measures showed no significant differences.

Rationale & Objective: About 25%-40% of patients with inflammatory bowel disease (IBD) may have extraintestinal manifestations, mainly involving the liver, skin, and joints. Kidney involvement in patients with IBD has been reported, but there are no estimates of its prevalence in population-based studies in the United States. We compared the frequency of acute kidney injury (AKI) among hospitalizations with IBD with that among hospitalizations with collagen vascular diseases and hospitalizations with neither condition. Study Design: Retrospective, population-based cohort study. Setting & Participants: Healthcare Cost and Utilization Project-Nationwide Inpatient Sample database. Outcomes: AKI and AKI requiring dialysis. Analytical Approach: Regression models were used to compare the occurrence of AKI among groups. Inverse probability of treatment weighting was applied to balance groups on covariates. Results: The final sample comprised 5,735,804 hospitalizations, including 57,121 with IBD, 159,930 with collagen vascular diseases, and 5,518,753 with neither IBD nor collagen vascular diseases. AKI was observed in 13%, 15%, and 12.2% of hospitalizations with IBD, collagen vascular diseases, and the general population, respectively. When adjusting for demographic, hospital, and clinical characteristics using inverse probability of treatment weighting, hospitalizations with IBD had higher odds of being diagnosed with AKI than both those with collagen vascular diseases (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.27-1.38) and the general population (OR, 1.27; 95% CI, 1.23-1.31) and also had higher odds of being diagnosed with AKI requiring dialysis than those with collagen vascular diseases (OR, 1.59; 95% CI, 1.31-1.94) or than the general population (OR, 1.45; 95% CI, 1.25-1.68). Limitations: Cross-sectional analysis, underreporting of International Classification of Diseases codes, and analyses relevant to in-hospital stays only. Conclusions: The prevalence and risk of AKI among hospitalizations with IBD is greater than that of hospitalizations with collagen vascular diseases and the general population. Coexisting kidney disease should be considered among patients with a known diagnosis of IBD. Plain Language Summary: As a nephrologist, we have evaluated many patients with inflammatory bowel disease with various forms of kidney disease, both inflammatory and noninflammatory. Based on a multitude of factors, we have always wondered if there are shared immune mechanisms between the gut and kidney that could explain the underlying inflammation in both organs. In addition, based on recent studies of other autoimmune/inflammatory diseases, there is growing interest in the role of the gut microbiome (microorganisms that reside in our gut) and its influence on the immune system as well as how both the altered microbiome and immune system affect the kidneys. As a first step, we wanted to understand if some forms of kidney disease are more prevalent in patients with inflammatory bowel disease than in the general population, which possibly suggests a shared pathogenesis.

The role of stressors, insect bites, and infections on disease relapse of ANCA vasculitis has yet to be entirely explored, with limited retrospective studies focused on disease onset from small participant cohorts. Our study analyzes longitudinal survey data from 2011–2022 to evaluate this perspective from a large ANCA vasculitis cohort. We collected surveys every three to six months to obtain information on self-reported psychological stressors and significant life events, insect bites, and infections throughout clinical disease. We defined cohorts as those who relapsed (Relapse Cohort) and controls as those who did not relapse (Remission Cohort) during the study period. Survey responses were retrospectively reviewed during a 15-month timeframe prior to relapse or during 15 months of remission and categorized by type of stress event, insect bite, and infections at every available 3-month interval. There were no significant differences in stress and insect bites between the relapse and remission cohorts. Patients who relapsed reported more frequent upper respiratory infections and other infections, such as those affecting the skin and eyes, but there were no significant differences in the incidence of pulmonary or urinary infections compared to the remission cohort. There was a significant difference in reported upper respiratory infections 9 to 15 months prior to the relapse date, indicating a remote history of infections as a potentially significant physical stressor that may contribute to disease relapse. More frequent patient-reported infections, specifically upper respiratory infections, may contribute to patient vulnerability to relapse. Counseling and close monitoring of patients after infectious symptoms could aid in earlier detection of disease flares. Future studies are essential to further understand the importance of distal risk factors and how they impact relapse.

Abstract To better understand mechanisms of serotonin‐ (5‐HT) mediated vasorelaxation, isolated lateral saphenous veins from cattle were assessed for vasoactivity using myography in response to increasing concentrations of 5‐HT or selective 5‐HT receptor agonists. Vessels were pre‐contracted with 1 × 10−4 M phenylephrine and exposed to increasing concentrations of 5‐HT or 5‐HT receptor agonists that were selective for 5‐HT1B, 5‐HT2B, 5‐HT4, and 5‐HT7. Vasoactive response data were normalized as a percentage of the maximum contractile response induced by the phenylephrine pre‐contraction. At 1 × 10−7 M 5‐HT, a relaxation was observed with an 88.7% decrease (p

Abstract The brain derived‐neurotrophic factor (BDNF) Val66Met polymorphism causes functional changes in BDNF, and is associated with obesity and some psychiatric disorders, but its relationship to health‐related quality of life (HRQoL) remains unknown. This study examined, in youth with obesity, whether carriers of the BDNF Val66met polymorphism Met‐alleles (A/A or G/A) differed from noncarriers (G/G) on HRQoL. The participants were 187 adolescents with obesity. Ninety‐nine youth were carriers of the homozygous Val/Val (G/G) alleles, and 88 were carriers of the Val/Met (G/A) or Met/Met (A/A) alleles. Blood samples were drawn in the morning after an overnight fast for genotyping. HRQoL was measured using the Pediatric‐Quality of Life core version. Compared to carriers of the Val66Met Val (G/G) alleles, carriers of the Met‐Alleles reported significantly higher physical –HRQoL (p = 0.02), school‐related HRQoL, (p = 0.05), social‐related HRQoL (p = 0.05), and total HRQoL (p = 0.03), and a trend for Psychosocial‐HRQoL. Research is needed to confirm our findings and determine whether carriers of the BDNF Val66Met homozygous Val (G/G) alleles may be at risk of diminished HRQoL, information that can influence interventions in a high‐risk population of inactive youth with obesity.

Individuals with lupus nephritis (LN) are at high risk of adverse maternal and fetal outcomes in pregnancy. Outside of pregnancy, proliferative lesions on kidney biopsies are associated with disease progression, but these have not been consistently associated with increased risk in pregnancy. This retrospective, single-center study examines how histologic findings, the timing from kidney biopsy to pregnancy, and the clinical features in the first trimester are associated with preterm birth among individuals with LN. Among 35 deliveries in 31 women, the mean gestational age at delivery was 33.8 weeks. The presence of a urine protein-to-creatinine ratio >0.5 g/g in the first trimester was associated with preterm delivery (81% vs. 36%, p = 0.04). Preterm birth was more common in individuals with glomerular crescents on biopsy (89% in those with >20% crescents vs. 50% in those with

Purpose: Individuals who do not complete substance use disorder treatment (SUDT) have similar outcomes to the untreated. Recovery capital (RC) is the collection of one’s resources that contribute to the initiation and maintenance of sobriety. The aim of this paper was to identify individual measures of RC that are associated with SUDT completion. Methods: RC data for 69 residents from a men’s recovery center was obtained from questionnaires administered to residents at intake and after SUDT graduation or dismissal. Participant data was divided into two groups, Graduates (n = 39, age 35.87±10.83) and Non-Graduates (n = 30, age 34.35±14.44), and retrospectively analyzed to compare RC between groups at various points during SUDT and which RC measures are associated with SUDT completion. Results: At baseline all participants reported limited RC and there was no significant difference in RC between groups. At graduation, Graduates reported significantly more RC in all measures when compared to baseline and Non-Graduates at dismissal. Non-Graduates reported a significant increase in Checking and Savings at dismissal but no other measure. Conclusion: Baseline levels of RC in both groups were limited and not significantly different which limited the capacity of the study to identify measures of RC associated with SUDT completion. A lack of RC at onset of SUDT did not preclude SUDT completion and obtaining RC during SUDT was associated with completion as only Graduates reported increases in RC. Future study designs should include participants with variable amounts of RC when entering SUDT.

Abstract High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease, and a highstromal/desmoplastic tumor microenvironment (TME) is associated with a poor outcome. Stromal cell subtypes, including fibroblasts, myofibroblasts, and cancer-associated mesenchymal stem cells, establish a complex network of paracrine signaling pathways with tumor-infiltrating immune cells that drive effector cell tumor immune exclusion and inhibit the antitumor immune response. In this work, we integrate single-cell transcriptomics of the HGSOC TME from public and in-house datasets (n = 20) and stratify tumors based upon high vs. low stromal cell content. Although our cohort size is small, our analyses suggest a distinct transcriptomic landscape for immune and non-immune cells in high-stromal vs. low-stromal tumors. High-stromal tumors have a lower fraction of certain T cells, natural killer (NK) cells, and macrophages, and increased expression of CXCL12 in epithelial cancer cells and cancer-associated mesenchymal stem cells (CA-MSCs). Analysis of cell-cell communication indicate that epithelial cancer cells and CA-MSCs secrete CXCL12 that interacte with the CXCR4 receptor, which is overexpressed on NK and CD8+ T cells. Dual IHC staining show that tumor infiltrating CD8 T cells localize in proximity of CXCL12+ tumor area. Moreover, CXCL12 and/or CXCR4 antibodies confirm the immunosuppressive role of CXCL12-CXCR4 in high-stromal tumors.

Abstract Snow and ice topography impact and are impacted by fluxes of mass, energy, and momentum in Arctic sea ice. We measured the topography on approximately a 0.5 km2 drifting parcel of Arctic sea ice on 42 separate days from 18 October 2019 to 9 May 2020 via Terrestrial Laser Scanning (TLS). These data are aligned into an ice-fixed, lagrangian reference frame such that topographic changes (e.g., snow accumulation) can be observed for time periods of up to six months. Using in-situ measurements, we have validated the vertical accuracy of the alignment to ± 0.011 m. This data collection and processing workflow is the culmination of several prior measurement campaigns and may be generally applied for repeat TLS measurements on drifting sea ice. We present a description of the data, a software package written to process and align these data, and the philosophy of the data processing. These data can be used to investigate snow accumulation and redistribution, ice dynamics, surface roughness, and they can provide valuable context for co-located measurements.

Injury or disease often compromise walking dynamics and negatively impact quality of life and independence. Assessing methods to restore or improve pathological gait can be expedited by examining a global parameter that reflects overall musculoskeletal control. Center of mass (CoM) kinematics follow well-defined trajectories during unimpaired gait, and change predictably with various gait pathologies. We propose a method to estimate CoM trajectories from inertial measurement units (IMUs) using a bidirectional Long Short-Term Memory neural network to evaluate rehabilitation interventions and outcomes. Five non-disabled volunteers participated in a single session of various dynamic walking trials with IMUs mounted on various body segments. A neural network trained with data from four of the five volunteers through a leave-one-subject out cross validation estimated the CoM with average root mean square errors (RMSEs) of 1.44cm, 1.15cm, and 0.40cm in the mediolateral (ML), anteroposterior (AP), and inferior/superior (IS) directions respectively. The impact of number and location of IMUs on network prediction accuracy was determined via principal component analysis. Comparing across all configurations, three to five IMUs located on the legs and medial trunk were the most promising reduced sensor sets for achieving CoM estimates suitable for outcome assessment. Lastly, the networks were tested on data from an individual with hemiparesis with the greatest error increase in the ML direction, which could stem from asymmetric gait. These results provide a framework for assessing gait deviations after disease or injury and evaluating rehabilitation interventions intended to normalize gait pathologies.

Abstract Background Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder resulting from pathogenic variants in three distinct genes, with most of the variants occurring in the electron transfer flavoprotein-ubiquinone oxidoreductase gene (ETFDH). Recent evidence of potential founder variants for MADD in the South African (SA) population, initiated this extensive investigation. As part of the International Centre for Genomic Medicine in Neuromuscular Diseases study, we recruited a cohort of patients diagnosed with MADD from academic medical centres across SA over a three-year period. The aim was to extensively profile the clinical, biochemical, and genomic characteristics of MADD in this understudied population. Methods Clinical evaluations and whole exome sequencing were conducted on each patient. Metabolic profiling was performed before and after treatment, where possible. The recessive inheritance and phase of the variants were established via segregation analyses using Sanger sequencing. Lastly, the haplotype and allele frequencies were determined for the two main variants in the four largest SA populations. Results Twelve unrelated families (ten of White SA and two of mixed ethnicity) with clinically heterogeneous presentations in 14 affected individuals were observed, and five pathogenic ETFDH variants were identified. Based on disease severity and treatment response, three distinct groups emerged. The most severe and fatal presentations were associated with the homozygous c.[1067G > A];c.[1067G > A] and compound heterozygous c.[976G > C];c.[1067G > A] genotypes, causing MADD types I and I/II, respectively. These, along with three less severe compound heterozygous genotypes (c.[1067G > A];c.[1448C > T], c.[740G > T];c.[1448C > T], and c.[287dupA*];c.[1448C > T]), resulting in MADD types II/III, presented before the age of five years, depending on the time and maintenance of intervention. By contrast, the homozygous c.[1448C > T];c.[1448C > T] genotype, which causes MADD type III, presented later in life. Except for the type I, I/II and II cases, urinary metabolic markers for MADD improved/normalised following treatment with riboflavin and L-carnitine. Furthermore, genetic analyses of the most frequent variants (c.[1067G > A] and c.[1448C > T]) revealed a shared haplotype in the region of ETFDH, with SA population-specific allele frequencies of

Nearly every aspect of our life is impacted by digital technologies manufactured and sold by companies. Legislative frameworks to limit the harms of such technologies have been slow to develop and remain entangled in controversy.1 The expanding role of digital technologies has been accompanied by a disturbing descent into authoritarianism in many countries that is also, in part, fueled by these very same tools.2 The decline of liberal democratic institutions is said to be linked to various properties of the digital ecosystem—from security flaws in popular applications used by states to engage in covert and remote surveillance3 to the development and exploitation of social media algorithms that push violent and divisive content.4 There is no doubt, then, that digital accountability research—which we define as evidence-based research seeking to track and expose risks to civil society in the digital ecosystem—is critical. This essay highlights the legal and ethical challenges faced in digital accountability research and concludes that a comprehensive and global ethical framework for such research is a critical step forward. As legal frameworks and norms continue to shift with respect to digital accountability research, such collaborative, international norm-setting would help ensure that digital accountability research continues.

AbstractGiven any two graphs F and H, the Ramsey number R(F, H) is defined as the smallest positive integer n such that every red-blue coloring of the edges of the complete graph Kn of order n, there will be a subgraph of Kn isomorphic to F whose edges are all colored red (a red F) or a subgraph of Kn isomorphic to H whose edges are all colored blue (a blue H). If F and H are bipartite graphs, then the k-Ramsey number [Formula: see text] is defined as the smallest positive integer n such that for any red-blue coloring of the edges of the complete k-partite graph of order n in which each partite set is of order [Formula: see text] or [Formula: see text] there will be a subgraph isomorphic to F whose edges are all colored red (a red F) or a subgraph isomorphic to H whose edges are all colored blue (a blue H). Andrews, Chartrand, Lumduanhom and Zhang found the k-Ramsey number [Formula: see text] for [Formula: see text], and for [Formula: see text] and [Formula: see text] where [Formula: see text]. We continue their work by investigating the case where the graphs F and H are both C5.

Extraintestinal salmonellosis can occur as a complication of enteric fever. In this case series, five clinically suspected cases of pyogenic meningitis and arthritis, a case of pyelonephritis suspected to be pyogenic or tubercular, a case of vertebral osteomyelitis suspected to be tuberculosis or malignancy, and a case of pyomyositis that clinically presented as a tumour were discussed. Although none of these cases were clinically suspected to be due to Salmonella, all were confirmed as extraintestinal salmonellosis based on microbiological evaluation. Salmonella should be suspected in acute inflammatory lesions that are unresponsive to empirical treatment. Instead of empirical antibiotics, culture and sensitivity-based antibiotics for the recommended duration are the only way to cure extraintestinal salmonellosis and prevent morbidity. Effective communication and correlation between the laboratory, clinician, and radiologist are essential for a definitive diagnosis. Histopathological and microbiological investigations should be done simultaneously to identify the definitive aetiology in all localised lesions presenting with necrosis/inflammatory response. This case series presents five cases of extraintestinal salmonellosis with serious complications, including meningitis, pyelonephritis, osteomyelitis, septic arthritis, and pyomyositis, each with varied clinical presentations.